WO2021147854A1 - Préparations d'anticorps monoclonaux anti-tigit recombinants entièrement humains, leur procédé de préparation et leur utilisation - Google Patents

Préparations d'anticorps monoclonaux anti-tigit recombinants entièrement humains, leur procédé de préparation et leur utilisation Download PDF

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WO2021147854A1
WO2021147854A1 PCT/CN2021/072690 CN2021072690W WO2021147854A1 WO 2021147854 A1 WO2021147854 A1 WO 2021147854A1 CN 2021072690 W CN2021072690 W CN 2021072690W WO 2021147854 A1 WO2021147854 A1 WO 2021147854A1
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antibody
preparation
liquid
antibody preparation
tigit
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PCT/CN2021/072690
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English (en)
Chinese (zh)
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张海桃
马丽强
汪音爵
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信达生物制药(苏州)有限公司
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Priority to US17/793,503 priority Critical patent/US20230080706A1/en
Priority to EP21744016.3A priority patent/EP4094777A4/fr
Priority to CN202180010322.2A priority patent/CN115052622A/zh
Priority to CA3168600A priority patent/CA3168600A1/fr
Priority to AU2021211799A priority patent/AU2021211799A1/en
Priority to JP2022544137A priority patent/JP2023511356A/ja
Publication of WO2021147854A1 publication Critical patent/WO2021147854A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of antibody preparations. More specifically, the present invention relates to an antibody (also called anti-TIGIT antibody) comprising a recombinant fully human anti-T cell immune receptor containing an immunoglobulin motif and an immunoreceptor tyrosine inhibitory motif domain
  • an antibody also called anti-TIGIT antibody
  • Drug stability is one of the important indicators to ensure the effectiveness and safety of drugs. Obtaining a good formulation prescription is a key condition to ensure that the drug maintains its effectiveness and safety during the shelf life.
  • TIGIT T cell immune receptor containing immunoglobulin motif and immunoreceptor tyrosine inhibitory motif domain, also known as WUCAM, Vstm3 or Vsig9
  • WUCAM immunoglobulin motif and immunoreceptor tyrosine inhibitory motif domain
  • Vsig9 T cell immune receptor containing immunoglobulin motif and immunoreceptor tyrosine inhibitory motif domain
  • the present invention meets the above-mentioned needs by providing a pharmaceutical preparation containing an antibody that specifically binds to TIGIT.
  • the antibody preparation of the present invention exhibits excellent stability against various stability influencing factors (such as temperature, repeated freezing and thawing, and shaking).
  • the present invention provides a liquid antibody preparation comprising (i) an anti-TIGIT antibody protein; (ii) a buffer, (iii) a stabilizer, and (iv) a surfactant.
  • the anti-TIGIT antibody comprises a heavy chain variable region VH and a light chain variable region VL, wherein the heavy chain variable region comprises the sequence of SEQ ID NO: 7 or a sequence having at least 90% identity therewith, and
  • the light chain variable region includes the sequence of SEQ ID NO: 8 or a sequence that is at least 90% identical to it:
  • the anti-TIGIT antibody comprises:
  • the anti-TIGIT antibody is an IgG4 type antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the sequence of SEQ ID NO: 9 or a sequence that is at least 90% identical to it, and wherein The light chain includes the sequence of SEQ ID NO: 10 or a sequence that is at least 90% identical to it:
  • the anti-TIGIT antibody is the anti-TIGIT monoclonal antibody ADI-30278 disclosed in PCT Application No. PCT/CN2019/097665 (International Filing Date: July 25, 2019), which is composed of SEQ ID NO: 9
  • the heavy chain sequence and the light chain sequence of SEQ ID NO: 10 are composed.
  • the anti-TIGIT antibody is an anti-TIGIT antibody recombinantly expressed in 293 cells or CHO cells.
  • the concentration of the anti-TIGIT antibody in the liquid antibody preparation of the present invention is about 1-150 mg/ml. In another embodiment, the concentration of the anti-TIGIT antibody in the liquid antibody preparation of the present invention is about 10-100 mg/ml, preferably 20-60 mg/ml, especially about 50 mg/ml. In other embodiments, the concentration of the anti-TIGIT antibody in the liquid antibody formulation of the present invention is about 10, 15, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, or 100 mg/ml.
  • the concentration of the buffer in the liquid antibody formulation of the present invention is about 5-50 mM. In one embodiment, the concentration of the buffer in the liquid antibody formulation of the present invention is about 5-30 mM, for example, about 5, 10, 15, 20, 25, 30 mM. In one embodiment, the buffer is a histidine buffer, and preferably, the buffer consists of histidine and histidine hydrochloride. In a preferred embodiment, the buffer is about 5-30 mM histidine buffer, for example 10-20 mM, such as about 10 mM histidine.
  • the concentration of the stabilizer in the liquid antibody formulation of the present invention is about 50-500 mM. In one embodiment, the concentration of the stabilizer in the liquid antibody formulation of the present invention is about 100-400 mM, for example about 100, 150, 200, 250, 300, 350, 400 mM.
  • the stabilizer is selected from polyols (e.g., sorbitol), sugars (e.g., sucrose), amino acids (e.g., arginine or arginine hydrochloride), and any combination thereof.
  • the stabilizer contains about 20-80 mg/ml sorbitol, such as 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80 mg/ml sorbitol.
  • the stabilizer contains about 20-60 mg/ml sucrose, for example, 20, 30, 40, 50, 60 mg/ml sucrose.
  • the stabilizer further comprises arginine, such as about 25mM-200mM, such as 50-150mM, or 50mM-120mM, preferably about 60-100mM, for example, about 60, 65, 70, 75, 80, 85, 90mM arginine.
  • arginine as a stabilizer is provided by arginine hydrochloride.
  • the stabilizer comprises a combination of sorbitol and arginine; or a combination of sucrose and arginine.
  • a combination of about 20-40 mg/ml sorbitol and about 50-100 mM arginine, or about 30-60 mg/ml sucrose and about 50-100 mM arginine may be used.
  • the liquid antibody formulation of the present invention contains about 30-60 mg/ml (such as about 50 mg/ml) sorbitol, or about 20-30 mg/ml (such as about 25 mg/ml) sorbitol and 80-90 mM (Approximately 85mM) Arginine.
  • the concentration of the surfactant in the liquid antibody preparation of the present invention is about 0.1-1 mg/ml. In one embodiment, the concentration of the surfactant in the liquid antibody preparation of the present invention is about 0.2-0.8 mg/ml, for example, about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 mg/ml.
  • the surfactant is a nonionic surfactant. In one embodiment, the surfactant is selected from polysorbate surfactants. In a specific embodiment, the surfactant in the liquid antibody formulation of the present invention is polysorbate-80.
  • the pH of the liquid formulation is about 5.0-6.0. In some embodiments, the pH of the liquid formulation is about any value from 5.0 to 6.0, for example, about 5.0, 5.2, 5.4, 5.6, 5.8, 6.0. Preferably, the pH of the formulation is 5.2 ⁇ 0.2 or 5.5 ⁇ 0.2, preferably the pH is 5.2.
  • the liquid antibody preparation of the invention comprises:
  • Histidine buffer of about 5-50 mM, such as 5-30 mM, such as 5, 10, 15, 20, 25, 30 mM;
  • polysorbate 80 for example, 0.1, 0.2.0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mg/ml;
  • the pH of the liquid formulation is about 5.0-5.5, for example, about 5.2.
  • the liquid antibody preparation may contain
  • anti-TIGIT antibody protein such as 20, 30, 40, 50, 55, 60 mg/ml;
  • the pH of the liquid formulation is about 5.0-5.5, for example, about 5.2.
  • the liquid antibody preparation comprises:
  • the liquid formulation of the present invention can be stored stably for a long period of time, for example, at least 24 months or more.
  • the liquid formulation of the present invention can be heated at about -80°C to about 45°C, for example -80°C, about -30°C, about -20°C, about 0°C, about 5°C, about 25°C, about Store at 35°C, about 38°C, about 40°C, about 42°C or about 45°C for at least 10 days, at least 20 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months , At least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months , At least 36 months, or longer, and stable.
  • the liquid formulation of the present invention can be stored stably for at least 24 months.
  • the liquid formulation of the present invention is stable at at least 40°C.
  • the liquid formulation of the present invention is stable at about 2°C-8°C for at least 3 months, preferably at least 12 months, and more preferably at least 24 months.
  • the liquid formulation of the present invention is stable at room temperature or, for example, about 25°C for at least 2 months, preferably at least 3 months, and more preferably at least 6 months.
  • the liquid formulation of the present invention remains stable at about 40°C for at least 2 weeks, preferably at least 1 month.
  • the stability of the preparation can be indicated by detecting changes in the appearance, visible foreign matter, protein content, turbidity, purity, and/or charge variants of the preparation. In one embodiment, it can be in a forced experiment of high temperature stress, for example after storage at 40°C ⁇ 2°C for at least 1 week, 2 weeks or preferably 1 month, or in an accelerated experiment, such as at 25°C ⁇ 2°C After storage for at least 1 month or 2 months, or in long-term experiments, such as storage at 5°C ⁇ 3°C for at least 2 months or 3 months, or in shaking experiments (for example, at room temperature, protected from light, 650r/min Under the conditions of shaking for 5 days), and/or in a freeze-thaw experiment (for example, repeated freeze-thaw at -30°C/room temperature 6 times), the stability of the liquid preparation of the present invention is tested. In one embodiment, the stability of the liquid formulation of the present invention is tested relative to the initial value, for example, the initial value on day 0 of storage, or the
  • the stability of the liquid formulation of the present invention is visually checked, wherein the liquid formulation of the present invention remains clear to slightly opalescent in appearance , It is a colorless to light yellow liquid with no foreign matter. In one embodiment, under a visual inspection under a clarity detector, no visible foreign matter is present in the preparation.
  • the stability of the liquid formulation of the present invention is checked by measuring the change in protein content, for example, by ultraviolet spectrophotometry (UV), relative From the initial value, the protein content change rate is not more than 20%, preferably not more than 10%, such as 7-8%, more preferably not more than 5%, 2% or 1%.
  • the stability of the liquid formulation of the present invention is checked by measuring the turbidity change of the liquid formulation of the present invention, for example, by the OD 350mm method.
  • the change value does not exceed 0.06, preferably does not exceed 0.05, more preferably does not exceed 0.04, and does not exceed 0.02.
  • the stability of the liquid formulation of the present invention is checked by measuring the change in purity of the liquid formulation of the present invention, wherein the stability of the liquid formulation of the present invention is checked by the size exclusion Chromatography (SEC-HPLC), relative to the initial value, the change value of monomer purity (or main peak change value) does not exceed 10%, such as not more than 5%, 4%, 3%, for example, the change value does not exceed 2%, Preferably it does not exceed 1%.
  • the stability of the liquid preparation of the invention is checked by measuring the purity change of the liquid preparation of the invention, wherein the stability of the liquid preparation of the invention is checked by non-reduced dodecane Based on sodium sulfate capillary electrophoresis (CE-SDS) method, relative to the initial value, the change value of the monomer purity (or the main peak change value) is reduced by no more than 10%, for example, no more than 5%, 4%, 3%, 2% or 1%.
  • CE-SDS sodium sulfate capillary electrophoresis
  • the stability of the liquid preparation of the present invention is tested by cation exchange high performance liquid chromatography (CEX-HPLC), which is relative to The initial value, the total change value of the antibody's charge variants (principal component, acidic component and basic component) does not exceed 50%, for example, does not exceed 40%, 30%, 20%, 10%, 5%, and/ Or the change value of the main component does not exceed 20%, 15%, 10%, 8%, 5%.
  • CEX-HPLC cation exchange high performance liquid chromatography
  • the stability of the liquid preparation of the present invention is tested by a direct ELISA method, wherein the relative binding activity of the antibody is 70 relative to the initial value. -130%, for example, 70, 80, 90, 93, 95, 98, 100, 103, 105, 108, 110, 115, 120, 125, 130%, preferably 90-110%.
  • the liquid formulation of the present invention is stable after storage, for example, after storage at 25°C for at least 2 months, or after storage at 40°C ⁇ 2°C for 1 month, and preferably has one of the following characteristics or Multiple items: relative to the initial value on day 0 of storage,
  • the main peak change value is less than 1%, and/or the preparation has a purity of greater than 96%, preferably greater than 97%, 98%;
  • the main peak change value is less than 2%, and/or the preparation has a purity of greater than 96%, preferably greater than 97%, 98%;
  • the total change value after storage at 40°C ⁇ 2°C for 1 month does not exceed about 40% (for example, not more than 35%, 30%, 25%, 20%, 15%, 10%) or the main component change value does not exceed 20% (for example, no more than 15%, 12%, 10%, 8%), or
  • the total change value does not exceed about 20% (for example, not more than 15%, 14%, 13%, 12%) or the main component change value does not exceed about 15% (for example, not more than 10 %, 8%, 7%, 6%, 5%);
  • the relative binding activity of the anti-TIGIT antibody protein in the preparation is 70%-130%, for example, 90,93,95,98,100,103,105,108,110,115,120%, for example, 90%-110%;
  • the liquid formulation of the present invention is stable under shaking and/or repeated freezing and thawing.
  • the preparation is stable under shaking or repeated freezing and thawing, for example, after shaking for 5 days under the condition of 650r/min at room temperature and avoiding light, or after repeated freezing and thawing at -30°C/room temperature for 6 times, it has the following characteristics:
  • the main peak change value is less than 1%, and/or the preparation has a purity greater than 96%, preferably greater than 97%, 98%, 99%;
  • the main peak change value is less than 1%, and/or the preparation has a purity of greater than 96%, preferably greater than 97%, 98%;
  • the relative binding activity of the anti-TIGIT antibody protein in the preparation is 70%-130%, for example, 90%-110%;
  • the liquid preparation of the present invention is a pharmaceutical preparation, preferably an injection, more preferably a subcutaneous injection or an intravenous injection.
  • the liquid formulation is an intravenous infusion agent.
  • the present invention provides a solid antibody preparation, which is obtained by subjecting the liquid antibody preparation of the present invention to a curing treatment.
  • the curing treatment is performed by, for example, a crystallization method, a spray drying method, or a freeze drying method.
  • the solid antibody preparation is, for example, in the form of a lyophilized powder injection.
  • the solid antibody preparation can be reconstituted in a suitable solvent before use to form the reconstituted preparation of the present invention.
  • the reconstituted preparation is also a liquid antibody preparation of the present invention.
  • the appropriate solvent is selected from water for injection, organic solvent for injection, including but not limited to oil for injection, ethanol, propylene glycol, etc., or a combination thereof.
  • the present invention provides a delivery device comprising the liquid antibody preparation or solid antibody preparation of the present invention.
  • the delivery device of the present invention is provided in the form of a pre-filled syringe containing the liquid antibody preparation or solid antibody preparation of the present invention, for example for intravenous, subcutaneous, intradermal or intramuscular injection, intravenous infusion .
  • the present invention provides a method for delivering an anti-TIGIT antibody protein to a subject, such as a mammal, comprising the step of administering the liquid antibody preparation or solid antibody preparation of the present invention to the subject, and the delivery is, for example, by Implemented using a delivery device with a pre-filled syringe.
  • the present invention provides the use of the liquid antibody preparation or solid antibody preparation of the present invention to prepare a delivery device or a preventive device that blocks the binding of TIGIT to CD155 in a subject to reduce or eliminate the immunosuppressive effect of TIGIT.
  • a delivery device or a preventive device that blocks the binding of TIGIT to CD155 in a subject to reduce or eliminate the immunosuppressive effect of TIGIT.
  • the tumors being, for example, cancers, including but not limited to the gastrointestinal tract Cancer, such as colon cancer.
  • the present invention also provides a liquid antibody preparation or solid antibody preparation of the present invention or a delivery device (such as a pre-filled syringe) or drug containing the liquid antibody preparation or solid antibody preparation of the present invention by administering the liquid antibody preparation or solid antibody preparation of the present invention to a subject.
  • a delivery device such as a pre-filled syringe
  • drug containing the liquid antibody preparation or solid antibody preparation of the present invention by administering the liquid antibody preparation or solid antibody preparation of the present invention to a subject.
  • the method of blocking the combination of TIGIT and CD155 to reduce or eliminate the immunosuppressive effect of TIGIT are examples of blocking the combination of TIGIT and CD155 to reduce or eliminate the immunosuppressive effect of TIGIT.
  • the present invention also provides a method for treating a subject by administering the liquid antibody preparation or solid antibody preparation of the present invention or a delivery device (such as a pre-filled syringe) or drug containing the liquid antibody preparation or solid antibody preparation to a subject Patients’ diseases, such as the above-mentioned tumor or pathogen infection methods.
  • a delivery device such as a pre-filled syringe
  • drug containing the liquid antibody preparation or solid antibody preparation to a subject Patients’ diseases, such as the above-mentioned tumor or pathogen infection methods.
  • Figure 1 shows that in the pH screening experiment of Example 1, the change trend graph of the antibody charge variant-principal component under different pH conditions detected by the CEX-HPLC method.
  • FIG. 1 Shows that in the pH screening experiment of Example 1, the CEX-HPLC method was used to detect the change trend graph of the antibody charge variant-acidic component under different pH conditions (CEX-HPLC method).
  • Fig. 3 shows a graph showing the change trend of charge variants detected by the CEX-HPLC method in the 40°C stability confirmation experiment in Example 2.
  • Fig. 4 shows a graph showing the change trend of charge variants detected by the CEX-HPLC method in the 25°C stability confirmation experiment of Example 2.
  • the term “comprising” or “including” means including the stated elements, integers or steps, but does not exclude any other elements, integers or steps.
  • the term “comprises” or “includes” when used, unless otherwise specified, it also encompasses the situation consisting of the stated elements, integers or steps.
  • an antibody variable region that "comprises” a specific sequence when referring to an antibody variable region that "comprises” a specific sequence, it is also intended to encompass the antibody variable region composed of the specific sequence.
  • TIGIT refers to "T cell immune receptor containing Ig and ITIM domains".
  • the expression also includes variants, isotypes, homologs, and species homologs of TIGIT.
  • TIGIT is also called VSIG9, VSTM3, WUCAM.
  • the amino acid and nucleic acid sequences of human and murine GITR can be found in GenBank accession numbers NP_776160 (human amino acid sequence) and NP_001139797 (murine amino acid sequence).
  • the TIGIT protein may also include a fragment of TIGIT, such as a fragment containing an extracellular domain, such as a fragment that retains the ability to bind to any antibody of the present invention.
  • antibody is used in the broadest sense and refers to a protein containing an antigen binding site, encompassing natural antibodies and artificial antibodies of various structures, including but not limited to intact antibodies and antigen-binding fragments of antibodies.
  • the terms “whole antibody”, “full-length antibody”, “full antibody” and “whole antibody” are used interchangeably herein to refer to at least two heavy chains (H) and two Light chain (L) glycoprotein.
  • Each heavy chain is composed of a heavy chain variable region (abbreviated as VH herein) and a heavy chain constant region.
  • the heavy chain constant region is composed of three structural domains CH1, CH2 and CH3.
  • Each light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region.
  • the light chain constant region consists of a domain CL.
  • the VH and VL regions can be further divided into hypervariable regions (complementarity determining regions (CDR)), with more conservative regions (framework regions (FR)) interposed between them.
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL consists of three CDRs and four
  • the FR composition is arranged in the following order from the amino terminal to the carboxy terminal: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • the constant region does not directly participate in the binding of the antibody to the antigen, but displays a variety of effector functions.
  • human antibody or “fully human antibody” are used interchangeably herein and refer to antibodies that include variable regions in which both framework regions and CDR regions are derived from human germline immunoglobulin sequences. Moreover, if the antibody contains a constant region, the constant region is also derived from human germline immunoglobulin sequences.
  • the human antibodies of the present invention may include amino acid sequences not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or point-specific mutagenesis in vitro or somatic mutations in vivo), such as in CDRs, especially in CDR3.
  • the term "human antibody” does not include antibodies in which CDR sequences are derived from the germline of other mammalian species (eg, mice) and transplanted into human framework sequences.
  • antibody preparation refers to a preparation that is in a form that allows the biological activity of the antibody as an active ingredient to be effectively exerted, and does not contain unacceptable toxicity to the subject to which the preparation is to be administered. Other components. Such antibody preparations are usually sterile. Generally, pharmaceutically acceptable excipients are included in antibody preparations.
  • a "pharmaceutically acceptable" excipient is an agent that can be reasonably administered to a tested mammal so that an effective dose of the active ingredient used in the formulation can be delivered to the subject. The concentration of the excipient is adapted to the mode of administration, for example, it may be acceptable for injection.
  • anti-TIGIT antibody preparation is also abbreviated as "antibody preparation of the present invention” herein, and means a preparation containing an anti-TIGIT antibody protein as an active ingredient and a pharmaceutically acceptable excipient. After the anti-TIGIT antibody protein is combined with a pharmaceutically acceptable excipient, the anti-TIGIT antibody protein as the active ingredient is suitable for therapeutic or preventive administration to humans or non-human animals.
  • the antibody preparations of the present invention can be prepared, for example, as liquid preparations in aqueous form, for example, ready-to-use prefilled syringes, or prepared as lyophilized preparations by dissolving and/or suspending in a physiologically acceptable solution immediately before use. Reconstitution (ie, reconstitution).
  • the anti-TIGIT antibody protein preparation is in the form of a liquid preparation.
  • a “stable” antibody preparation means that the antibody in the preparation retains an acceptable degree of physical stability and/or chemical stability after being stored under specific conditions, or after shaking, or after repeated freezing and thawing. Although the antibody contained in the antibody preparation may not maintain 100% of its chemical structure after storage, shaking or repeated freezing and thawing, it is usually maintained at about 90%, about 95%, about 96%, about 97%, about 98%.
  • the antibody preparation is considered "stable.”
  • the anti-TIGIT antibody protein formulation of the present invention exhibits low to undetectable antibody aggregation or degradation or chemical modification during the manufacturing, preparation, transportation and long-term storage, so that there is little or no The biological activity of the anti-TIGIT antibody protein is lost, showing a high degree of stability.
  • the anti-TIGIT antibody protein preparation of the present invention substantially retains its physical and chemical stability after storage, shaking, and/or repeated freezing and thawing.
  • the liquid preparation of the present invention can be stable at room temperature or at 40°C for at least 2 weeks, and/or at 25°C for at least 2 months, and/or at 2-8°C for at least 24 months.
  • the liquid preparation of the present invention can be stable after shaking at 650 r/min at room temperature for 5 days and/or after repeated freezing and thawing at -30°C/room temperature for 1-6 times.
  • the stability can be measured at a selected temperature and selected storage time. For example, the storage time can be selected based on the expected shelf life of the formulation. Alternatively, an accelerated stability test can be used. In some embodiments, the stability test is performed by performing various stress tests on the antibody preparation.
  • the formulated anti-TIGIT antibody protein preparation can be filled into a glass vial to test the stability of the antibody under high temperature stress.
  • the formulated anti-TIGIT antibody protein preparation can be filled into a glass vial and shaken at 650 r/min at room temperature and protected from light for 5 days, and then the stability of the antibody can be checked.
  • the stability of the antibody is checked.
  • freezing and storing below -30°C for 1 day and then thawing at room temperature is a freeze-thaw cycle.
  • the preparation After a period of storage, or after shaking for a period of time, or after repeated freezing and thawing many times, the preparation does not show aggregation, precipitation, turbidity and/or denaturation; or shows very little aggregation, precipitation, turbidity and/or denaturation, then It can be said that the antibody "maintains its physical stability" in the formulation.
  • the accumulation of antibodies in the preparation can potentially lead to an increased immune response in patients, leading to safety issues. Therefore, there is a need to minimize or prevent aggregation of the antibody in the formulation.
  • the light scattering method can be used to determine the visible aggregates in the formulation.
  • SEC-HPLC can be used to determine soluble aggregates in the formulation.
  • the stability of the preparation can be indicated by visually inspecting the appearance, color, and/or clarity of the preparation, or detecting the turbidity of the preparation by the OD 350nm method, or measuring the purity of the preparation by the non-reducing CE-SDS method.
  • the stability of the formulation is measured by determining the percentage of antibody monomers in the formulation after storage at a specific temperature for a specific time or after shaking or after repeated freezing and thawing, wherein the percentage of antibody monomers in the formulation The higher, the higher the stability of the formulation.
  • “Acceptable degree” of physical stability can mean that at least about 90% of the anti-TIGIT antibody protein monomer is detected in the preparation after storage at a specific temperature for a specific time, after shaking or after repeated freezing and thawing.
  • an acceptable degree of physical stability indicates At least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the anti-TIGIT antibody protein monomer.
  • the specific temperature at which the pharmaceutical preparation is stored may be any temperature from about -80°C to about 45°C, for example, when stored at about -80°C, about -30°C, about -20°C, about 0°C, About 4°C-8°C, about 5°C, about 25°C, about 35°C, about 37°C, about 40°C, about 42°C, or about 45°C.
  • the pharmaceutical preparation is considered stable.
  • the pharmaceutical preparation is considered stable. If stored at about 25°C for 2 months, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the anti-TIGIT antibody protein list is detected Body, the pharmaceutical preparation is considered stable. If stored at about 5°C for 9 months, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% of the anti-TIGIT antibody protein list is detected. Body, the pharmaceutical preparation is considered stable.
  • the antibody in the preparation After a period of storage, or after shaking for a period of time, or after repeated freezing and thawing many times, if the antibody in the preparation does not show significant chemical changes, it can be considered that the antibody "maintains its chemical stability" in the preparation.
  • Most chemical instabilities result from the formation of covalently modified forms of antibodies (for example, charge variants of antibodies).
  • charge variants of antibodies for example, charge variants of antibodies.
  • chemical stability can be assessed by detecting and/or quantifying the chemically altered form of the antibody.
  • the charge variant of the antibody in the preparation can be detected by cation exchange chromatography (CEX) or imaging capillary isoelectric focusing electrophoresis (iCIEF).
  • CEX cation exchange chromatography
  • iCIEF imaging capillary isoelectric focusing electrophoresis
  • the stability of the formulation is measured by determining the percentage change in the charge variant of the antibody in the formulation after being stored at a specific temperature for a specific time or after shaking or repeated freezing and thawing several times, wherein the smaller the change is , The higher the stability of the formulation.
  • the "acceptable degree" of chemical stability can mean that the charge variants (such as the main component or acidic component or alkali) in the preparation after storage at a specific temperature for a specific period of time, or after shaking for a period of time, or after repeated freezing and thawing many times.
  • the percentage change value of the sexual component does not exceed 40%, such as not more than 30%, not more than 20%; or the sum of the percentage change values of the charge variants (main component, acidic component and alkaline component) does not exceed 60% , For example, no more than 50%, no more than 30%.
  • an acceptable degree of chemical stability can be The percentage change value of the main component charge variant does not exceed about 50%, 40%, 30%, 20%, or 15%; or the sum of the percentage change value of the charge variant does not exceed about 60%, 50%, or 30 %.
  • the storage temperature of the pharmaceutical preparation can be any temperature from about -80°C to about 45°C, for example, when stored at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C-8°C, about 5°C, about 25°C, or about 45°C.
  • the pharmaceutical preparation can be considered stable.
  • the pharmaceutical preparation can also be considered stable. If the percentage change value of the principal component charge variant is less than about 50%, 40%, 30%, 20%, 16%, 15%, 14%, 13%, 12%, 10%, 5%, or 4%, the pharmaceutical preparation can also be considered stable.
  • lyophilized preparation refers to a composition obtained or obtainable by freeze-drying a liquid preparation. Preferably, it is a solid composition having a water content of less than 5%, preferably less than 3%.
  • reconstituted preparation refers to a liquid preparation obtained by dissolving and/or suspending a solid preparation (for example, a lyophilized preparation) in a physiologically acceptable solution.
  • room temperature refers to a temperature of 15°C to 30°C, preferably 20°C to 27°C, more preferably 25°C.
  • Stress conditions refer to environments that are chemically and/or physically unfavorable to the antibody protein, which can lead to unacceptable instability of the antibody protein, for example, high temperature, shaking, freezing and thawing.
  • High temperature stress refers to storing the antibody preparation at room temperature or even at a higher temperature (for example, 40°C ⁇ 2°C) for a period of time. Through the accelerated test of high temperature stress, the stability of the antibody preparation can be checked.
  • parenteral administration means administration methods other than enteral and local administration, usually by injection or infusion, and includes, but is not limited to, intravenous, intramuscular, intraarterial, and intrathecal , Intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions .
  • the stabilized anti-TIGIT antibody protein formulation of the present invention is administered to the subject parenterally.
  • the anti-TIGIT antibody protein formulation of the present invention is administered to a subject by subcutaneous, intradermal, intramuscular, or intravenous injection.
  • the present invention provides a stable liquid antibody preparation comprising (i) an anti-TIGIT antibody, (ii) a buffer, (iii) a stabilizer, and (iv) a surfactant, and the pH of the antibody preparation is about 5.0-6.0.
  • the liquid antibody preparation of the present invention is in the form of an injection preparation.
  • an "anti-TIGIT antibody” refers to an antibody that can bind to a TIGIT molecule with sufficient affinity so that the antibody can be used as a therapeutic and/or preventive agent that targets the TIGIT molecule.
  • the anti-TIGIT antibody in the antibody preparation of the present invention can have a high affinity, for example, with a K of 10 -7 M or less, preferably 10-20 ⁇ 10 -10 M.
  • D specifically binds to human TIGIT, and thereby mediates efficient blocking of the binding of TIGIT and its ligand CD155, reducing or eliminating the inhibitory signal transduction caused by TIGIT binding to its ligand.
  • the anti-TIGIT antibody in the antibody preparation of the present invention inhibits the growth of tumors (such as gastrointestinal tumors, preferably colorectal cancer) containing infiltrating lymphocytes expressing human TIGIT, and is preferably used in combination with an anti-PD1 antibody ,
  • tumors such as gastrointestinal tumors, preferably colorectal cancer
  • an anti-PD1 antibody preferably used in combination with an anti-PD1 antibody .
  • the anti-tumor effect is significantly better than that when a single antibody is administered.
  • the anti-TIGIT antibody in the antibody preparation of the present invention comprises: SEQ ID NO: 7 or a heavy chain variable region (VH) with at least 90% identity; and SEQ ID NO: 8 or a heavy chain variable region (VH) A light chain variable region (VL) with at least 90% identity.
  • a "variable region” or “variable domain” is a domain in the heavy or light chain of an antibody that participates in the binding of the antibody to its antigen.
  • the heavy chain variable region (VH) and light chain variable region (VL) can be further divided into hypervariable regions (HVR, also known as complementarity determining regions (CDR)), with more conservative regions (ie , Framework area (FR)).
  • HVR hypervariable regions
  • CDR complementarity determining regions
  • FR Framework area
  • Each VH and VL consists of three CDRs and 4 FRs, arranged in the following order from the amino terminal to the carboxy terminal: FR1, CDR1, FR2, CDR2, FR3, CDR
  • the anti-TIGIT antibody in the antibody preparation of the present invention comprises the VH CDR1, 2 and 3 sequences in the heavy chain variable region shown in SEQ ID NO: 7 and the light chain variable region shown in SEQ ID NO: 8
  • the "complementarity determining region” or “CDR region” or “CDR” (herein can be used interchangeably with the hypervariable region “HVR”) is the amino acid region in the variable region of an antibody that is mainly responsible for binding to an epitope.
  • the CDRs of the heavy chain and light chain are usually referred to as CDR1, CDR2, and CDR3, and are numbered sequentially from the N-terminus.
  • the CDRs located in the variable domain of the antibody heavy chain are called VH CDR1, VH CDR2, and VH CDR3, and the CDRs located in the variable domain of the antibody light chain are called VL CDR1, VL CDR2, and VL CDR3.
  • Various schemes for determining the CDR sequence of a given VH or VL amino acid sequence are known in the art.
  • the Kabat complementarity determining region (CDR) is determined based on sequence variability and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. 1991)).
  • Chothia refers to the position of structural loops (Chothia and Lesk, J.
  • AbM HVR is a compromise between Kabat HVR and Chothia structural loops, and is used by Oxford Molecular's AbM antibody modeling software. "Contact” HVR is based on the analysis of available complex crystal structures. HVR can also be determined based on having the same Kabat numbering position as a reference CDR sequence (e.g., an exemplary CDR disclosed herein).
  • the anti-TIGIT antibody of the present invention has VH CDR1 of SEQ ID NO: 1, VH CDR2 of SEQ ID NO: 2, VH CDR3 of SEQ ID NO: 3; and VL CDR1 of SEQ ID NO: 4, SEQ VL CDR2 of ID NO: 5 and VL CDR3 of SEQ ID NO: 6.
  • the anti-TIGIT antibody in the antibody preparation of the present invention may comprise a heavy chain variable region (VH) having at least 90%, 95%, 98% or 99% or more identity with SEQ ID NO: 7 ; And/or a light chain variable region (VL) with at least 90%, 95%, 98%, or 99% or higher identity with SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • sequence identity refers to the degree of sequence identity on a nucleotide-by-nucleotide or amino acid-by-amino-acid basis in the comparison window.
  • the "percent sequence identity” can be calculated in the following way: the two best aligned sequences are compared in the comparison window, and the same nucleic acid bases (for example, A, T, C, G, I, etc.) are present in the two sequences. ) Or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) The number of positions to get the number of matching positions, the number of matching positions is divided by the total number of positions in the comparison window (ie, the window size), and the result is multiplied by 100 to produce the sequence identity percentage.
  • the optimal alignment to determine the percent sequence identity can be achieved in a variety of ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for sequence alignment, including any algorithms required to achieve the maximum alignment within the full-length sequence being compared or within the target sequence region.
  • the VH sequence of the antibody of the present invention has no more than 10, preferably no more than 5, 4 or 3 different residues compared to SEQ ID NO: 7, and preferably the different residues are Conservative amino acid substitutions.
  • the VL sequence of the antibody of the present invention has no more than 10, preferably no more than 5, 4 or 3 different residues compared to SEQ ID NO: 8, preferably the different residues are Conservative amino acid substitutions.
  • Constant substitution refers to an amino acid change that results in the substitution of a certain amino acid with a chemically similar amino acid. It is well known in the art to provide conservative substitution tables of functionally similar amino acids. In any embodiment of the present invention, in a preferred aspect, the conservatively substituted residues are derived from the conservative substitution table A below, preferably the preferred substituted residues shown in Table A.
  • the anti-TIGIT antibody in the antibody preparation of the invention is an antibody in the form of IgG.
  • Antibody in the form of IgG refers to the form of IgG to which the constant region of the heavy chain of the antibody belongs.
  • the heavy chain constant regions of all antibodies of the same IgG form are the same, and the heavy chain constant regions of antibodies of different IgG forms are different.
  • an antibody in the form of IgG1 means that the Ig domain of its heavy chain constant region is the Ig domain of IgG1.
  • the anti-TIGIT antibody in the antibody preparation of the present invention is the anti-TIGIT monoclonal antibody ADI-30278 disclosed in PCT application number PCT/CN2019/097665 (International filing date: July 25, 2019), It has a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10.
  • the anti-TIGIT antibody is a purified IgG4 type antibody produced by recombinant expression in CHO cells.
  • the antibody in the liquid formulation of the present invention exhibits significant anti-tumor activity. For example, in a mouse tumor model inoculated with mouse MC38 cells, administration of the antibody preparation of the present invention can lead to a significant tumor suppressing effect, especially when combined with an anti-PD-1 antibody.
  • the amount of the antibody or antigen-binding fragment thereof contained in the antibody preparation of the present invention may vary according to the specific purpose characteristics of the preparation, the specific environment, and the specific purpose for which the preparation is used.
  • the antibody preparation is a liquid preparation, which may contain about 1-150 mg/ml, preferably about 10-100 mg/mL, such as about 10, 15, 20, 25, 30, 35, 40, 50, 60. , 70, 80, 90 or 100mg/ml anti-TIGIT antibody.
  • the buffer is an agent that can maintain the pH of the solution within an acceptable range.
  • the buffering agent used in the formulation of the present invention can control the pH of the formulation of the present invention in a pH range of about 5.0-6.0, for example, a pH of about 5.0-5.5.
  • the antibody formulations of the invention have a pH of about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, or 5.8.
  • the antibody preparation of the present invention has a pH of 5.2 ⁇ 0.2 or 5.5 ⁇ 0.2, preferably a pH of 5.2.
  • the formulation of the present invention comprises a buffer system selected from the group consisting of histidine-histidine hydrochloride buffer system, citrate-sodium citrate buffer system, acetic acid-sodium acetate buffer system, phosphate buffer system , Preferably histidine-histidine hydrochloride buffer system.
  • the buffer used in the formulation of the present invention is a histidine buffer, especially a buffer system composed of histidine and histidine hydrochloride.
  • the concentration of histidine in the histidine buffer of the present invention is about 5-50 mM, especially about 5-30 mM, for example, about 5, 10, 15, 20, 25, 30 mM.
  • the formulation of the invention contains about 10 mM histidine.
  • the histidine buffer used in the formulation of the present invention consists of, for example, about 0.21 mg/ml histidine and about 1.81 mg/ml histidine hydrochloride.
  • Suitable stabilizers for use in the present invention may be selected from sugars, polyols and amino acids and combinations thereof.
  • Sugars used as stabilizers include, but are not limited to, sucrose, trehalose, maltose and combinations.
  • the polyol used as a stabilizer includes, but is not limited to, sorbitol, mannitol, or a combination thereof.
  • the amino acids used as stabilizers include, but are not limited to, arginine, arginine hydrochloride, methionine, glycine, proline, and combinations.
  • the stabilizer comprises one or more selected from the following:
  • -A polyol selected from sorbitol, mannitol, or a combination thereof, about 10-100 mg/ml, preferably 20-40 mg/ml, such as 25 mg/ml; or 40-60 mg/ml, such as 50 mg/ml;
  • -A sugar selected from sucrose, trehalose, maltose, or a combination thereof, for example, about 10-100 mg/ml, preferably 30-60 mg/ml, such as 40 mg/ml;
  • -Amino acids selected from arginine hydrochloride, methionine, glycine, proline and combinations thereof, for example, 20-200 mM, such as about 50-110 mM, for example, 70-100 mM, especially about 80-90 mM.
  • the liquid formulation of the present invention contains sucrose as a stabilizer.
  • the amount of sucrose in the liquid formulation of the present invention may be about 10-100 mg/ml, preferably 30-60 mg/ml, for example 40 mg/ml.
  • the liquid formulation of the present invention contains sorbitol as a stabilizer.
  • the amount of sorbitol in the liquid formulation of the present invention may be about 10-100 mg/ml, preferably 20-40 mg/ml, such as 25 mg/ml; or 40-60 mg/ml, such as 50 mg/ml.
  • the liquid formulation of the present invention contains arginine as a stabilizer.
  • the amount of arginine in the liquid preparation of the present invention may be about 50-110 mM, for example, 70-100 mM, especially about 80-90 mM, for example, about 17.91 mg/ml arginine hydrochloride.
  • the liquid formulation of the present invention contains sorbitol as a single stabilizer.
  • the amount of sorbitol in the liquid formulation of the present invention may be about 30-70 mg/ml, for example 40-60 mg/ml.
  • sorbitol may be present in an amount of about 30, 35, 40, 45, 50, 55, 60, 65 or 70 mg/ml, preferably in an amount of about 50 mg/ml.
  • the liquid formulation of the present invention contains a combination of sorbitol and arginine as a stabilizer.
  • sorbitol may be present in an amount of about 10-60 mg/ml, preferably 15-40 mg/ml, such as 20-35 mg/ml, for example, about 20, 21, 22, 23, 24, 25, 26 ,27,28,29,30mg/ml.
  • arginine may be present in an amount of about 70-100 mM, especially about 85 mM.
  • the liquid preparation of the present invention contains about 20-30 mg/ml sorbitol and about 15-20 mg/ml arginine hydrochloride. More preferably, the liquid formulation of the present invention contains about 25 mg/ml of sorbitol and about 17.91 mg/ml of arginine hydrochloride.
  • the liquid formulation of the present invention contains a combination of sucrose and arginine as a stabilizer.
  • sucrose may be present in an amount of about 10-60 mg/ml, preferably 20-50 mg/ml, such as 30-40 mg/ml, for example, it may be about 30, 32, 34, 36, 38, 40, 42. 44,46,48,50mg/ml.
  • arginine may be present in an amount of about 70-100 mM, especially about 85 mM.
  • the liquid preparation of the present invention contains about 30-50 mg/ml sucrose and about 15-20 mg/ml arginine hydrochloride. More preferably, the liquid preparation of the present invention contains about 40 mg/ml of sucrose and about 17.91 mg/ml of arginine hydrochloride.
  • surfactant refers to an organic substance with an amphiphilic structure; that is, they are composed of groups with opposite solubility tendencies, usually oil-soluble hydrocarbon chains and water-soluble ionic groups. group.
  • the surfactant in the liquid formulation of the present invention is a nonionic surfactant, for example, alkyl poly(ethylene oxide).
  • nonionic surfactants that can be included in the formulation of the present invention include, for example, polysorbates, such as polysorbate-20, polysorbate-80, polysorbate-60, or polysorbate-40; Sam et al.
  • the liquid formulation of the present invention contains polysorbate-80 as a surfactant.
  • the surfactants that can be used in the liquid formulations of the present invention include, but are not limited to, polysorbate surfactants (e.g., polysorbate 80, polysorbate 20), poloxamers, and polyethylene. Glycol.
  • the amount of the surfactant contained in the antibody preparation of the present invention can be changed according to the specific purpose characteristics of the preparation, the specific environment, and the specific purpose for which the preparation is used.
  • the formulation may contain about 0.01-5 mg/ml, preferably about 0.1-1 mg/ml, for example about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 mg/ml Surfactant, especially polysorbate-80, preferably about 0.5mg/ml polysorbate-80.
  • the antibody liquid formulation of the present invention optionally contains other excipients.
  • the other excipients include, for example, antimicrobial agents, antistatic agents, antioxidants, chelating agents, gelatin, and the like.
  • These and other known pharmaceutical excipients and/or additives suitable for the formulation of the present invention are well known in the art, for example, listed in "The Handbook of Pharmaceutical Excipients, 4th Edition, edited by Rowe et al., American Pharmaceuticals Association (2003); and Remington: the Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippincott Williams & Wilkins (2005)".
  • the present invention provides stable formulations containing anti-TIGIT antibody protein.
  • the anti-TIGIT antibody protein used in the formulation of the present invention can be prepared using techniques known in the art for antibody production. For example, antibodies can be produced recombinantly. In a preferred embodiment, the antibody of the present invention is recombinantly produced in 293 cells or CHO cells.
  • recombinantly produced monoclonal antibodies can be purified by conventional purification methods to provide pharmaceutical substances with sufficient reproducibility and moderate purity for the preparation of antibody preparations.
  • a commercially available protein concentration filter such as Amicon's ultrafiltration device can be used to concentrate the supernatant from the expression system.
  • the antibody can be purified using methods such as chromatography, dialysis, and affinity purification.
  • Protein A is suitable as an affinity ligand for the purification of IgG1, IgG2 and IgG4 type antibodies.
  • Other antibody purification methods such as ion exchange chromatography, can also be used.
  • a preparation containing the antibody can be prepared according to methods known in the art.
  • the following steps can be used for preparation: (1) After the fermentation, the fermentation broth is centrifuged to clarify impurities such as cells to obtain the supernatant; (2) affinity chromatography (for example, specific for IgG1, IgG2, and IgG4 antibodies) Affinity protein A column) capture antibody; (3) virus inactivation; (4) purification and purification (usually CEX cation exchange chromatography can be used) to remove impurities in the protein; (5) virus filtration (to make the virus titer) Reduce, for example, 4 log10 or more); (6) Ultrafiltration/diafiltration (can be used to replace the protein in a formulation buffer that is conducive to its stability and concentrate it to a suitable concentration for injection). See, for example, B. Minow, P. Rogge, K. Thompson, BioProcess International, Vol. 10, No. 6, 2012, pp. 48-57.
  • the stability research of biological products generally includes real-time stability research under actual storage conditions (long-term stability research), accelerated stability research and forced condition test research.
  • Stability research should explore and optimize the research conditions according to the research purpose and the product's own characteristics; for various influencing factors (such as temperature, repeated freezing and thawing, vibration, etc.), develop stability studies such as long-term, accelerated and/or forced condition tests Program. Accelerated and compulsory condition tests are helpful to understand the stability of the product under short-term deviation from storage conditions and extreme conditions, and provide supporting data for the determination of the expiration date and storage conditions.
  • antibodies may undergo aggregation, degradation, or chemical modification, resulting in antibody heterogeneity (including size heterogeneity and charge heterogeneity), aggregates and fragments, etc. Affect the quality of antibody preparations. Therefore, it is necessary to monitor the stability of antibody preparations.
  • Various methods are known in the art that can be used to test the stability of antibody preparations.
  • methods such as reduced CE-SDS, non-reduced CE-SDS, and SEC-HPLC can be used to analyze the purity of antibody preparations and evaluate the aggregation level of antibodies; capillary isoelectric focusing (cIEF), imaging capillary, etc.
  • Focused electrophoresis (iCIEF) and ion exchange chromatography (IEX) are used to analyze charge variants in antibody preparations.
  • the stability of the preparation can be quickly judged by visually inspecting the appearance of the preparation.
  • the OD 350nm method can also be used to detect changes in the turbidity of the preparation, which can give information about the amount of soluble and insoluble aggregates.
  • ultraviolet spectrophotometry UV method
  • UV method ultraviolet spectrophotometry
  • the non-reduced CE-SDS method is a method of antibody purity determination using capillary as a separation channel.
  • CE-SDS protein migration is driven by the surface charge caused by SDS binding, and the surface charge is proportional to the molecular weight of the protein. Since all SDS-protein complexes have similar mass-to-charge ratios, electrophoretic separation based on molecular size or hydrodynamic radius can be achieved in the molecular sieve gel matrix of the capillary. This method has been widely used to monitor the purity of denatured intact antibodies.
  • the test sample is mixed with SDS sample buffer and iodoacetamide.
  • the mixture can be incubated at 68-72°C for about 10-15 minutes, and the supernatant centrifuged after cooling to room temperature is used for analysis.
  • a UV detector is used to detect the migration of the protein and obtain an electrophoresis spectrum.
  • the purity of the antibody preparation can be calculated as the percentage of the peak area of the main IgG peak to the sum of all peak areas.
  • Size exclusion high performance liquid chromatography is another important method for antibody standards and quality control. This method is mainly based on the size of the molecule or the difference in hydrodynamic radius to separate the molecules.
  • SEC-HPLC antibodies can be separated into three main forms: high molecular weight form (HMMS), main peak (mainly antibody monomer), and low molecular weight form (LMMS).
  • HMMS high molecular weight form
  • LMMS low molecular weight form
  • Antibody purity can be calculated as the percentage of the main peak area on the chromatogram to the sum of all peak areas.
  • the SEC-HPLC method the percentage of antibody monomers in the preparation product can be measured, and the content information of soluble aggregates and shears can be given.
  • the charge variant of the antibody in the antibody preparation can be determined by cation exchange high performance liquid chromatography (CEX-HPLC).
  • CEX-HPLC cation exchange high performance liquid chromatography
  • the peaks eluted from the CEX-HPLC column earlier than the retention time of the main peak (or main component) are marked as “acidic peaks” (or acidic components), and those with a retention time greater than that of the main peak
  • the peaks eluted from the CEX-HPLC column later are labeled as "basic peaks” (or basic components).
  • Accelerated stability studies can be used to check the stability properties of products, which is conducive to the screening of stable pharmaceutical formulations.
  • a sample of the formulation can be placed at an elevated temperature, such as about 40°C ⁇ 2°C, 25°C ⁇ 2°C, for accelerated stability studies.
  • shaking experiments or repeated freezing and thawing experiments can be performed to test the stability properties of the product. For example, oscillate at 650r/min at room temperature and avoid light for 1-5 days to perform an oscillation experiment.
  • a product frozen at -30°C for one day and then thawing at room temperature can be used as a freeze-thaw cycle, and repeated freeze-thaw experiments can be performed, in which repeated freeze-thaw cycles can be implemented 1-6 times.
  • the detection indicators of product stability can include appearance, visible foreign matter, protein content, turbidity, purity (SEC-HPLC method, non-reduced CE-SDS method) and charge variants (iCIEF method, CEX-HPLC method).
  • the efficacy or biological activity of the antibody can be tested.
  • the binding ability of the antibody and its antigen molecule (TIGIT) in the preparation can be tested.
  • TIGIT antigen molecule
  • the antibody preparation of the present invention containing the anti-TIGIT antibody protein of the present invention has reduced immunosuppression, and can be used to treat or prevent tumors, pathogen infections, and the like.
  • the formulation of the present invention can be used to block the binding of TIGIT to CD155 in a subject to reduce or eliminate the immunosuppressive effect of TIGIT.
  • the formulations of the present invention can be used to treat or prevent tumors and pathogen infections in subjects.
  • the tumor is, for example, a gastrointestinal cancer, such as colon cancer.
  • the formulation of the invention may be administered in combination with a second therapeutic agent, such as an anti-PD-1 antibody.
  • the present invention also provides the use of the preparation of the present invention in the preparation of medicines, wherein the medicines are used to deliver anti-TIGIT antibody proteins to mammals.
  • the present invention also provides a method for the preparation of the present invention to treat or prevent one or more of the above-mentioned diseases and diseases.
  • the mammal is a human.
  • the antibody formulation of the present invention can be administered to a subject or patient in a variety of ways.
  • administration can be by infusion or by syringe.
  • the present invention provides a delivery device (e.g., a syringe) comprising the antibody preparation of the present invention (e.g., a pre-filled syringe).
  • the patient will receive an effective amount of anti-TIGIT antibody protein as the main active ingredient, that is, an amount sufficient to treat, ameliorate or prevent the target disease or condition.
  • the therapeutic effect may include reducing physical symptoms.
  • the optimal effective amount and concentration of antibodies for any particular subject will depend on many factors, including the patient’s age, weight, health and/or gender, the nature and extent of the disease, the activity of the particular antibody, and the body’s Its clearance rate, and also includes any possible other treatments administered in combination with the antibody formulation. For specific situations, the effective amount delivered can be determined within the judgment of the clinician.
  • Recombinant fully human anti-TIGIT monoclonal antibody ADI-30278 is an antibody independently developed by Cinda Biopharmaceutical (Suzhou) Co., Ltd. and is disclosed in PCT application number PCT/CN2019/097665.
  • the antibody can effectively block the binding of TIGIT to its ligand CD155, relieve the inhibitory effect of CD155 on the downstream IL2 signaling pathway, and inhibit tumor growth when administered in vivo, especially when combined with anti-PD-1 antibody, the tumor suppressor effect Especially remarkable.
  • N/A means not applicable.
  • the inspection items during the whole research process mainly include: (1) detection of appearance and presence of visible foreign matter; (2) determination of protein content in preparations by ultraviolet method (UV method); (3) detection of turbidity of preparations by OD350nm method; 4) Determine the purity of the antibody preparation by size exclusion high performance liquid chromatography (SEC-HPLC), expressed as the percentage of the area of the main peak to the sum of all peak areas; (5) Pass the non-reduced sodium lauryl sulfate capillary Electrophoresis (non-reduced CE-SDS) was used to determine the purity of the antibody preparation, expressed as the percentage of the area of the main peak to the sum of all peak areas; (6) The charge variant in the antibody preparation was measured by CEX-HPLC method, expressed as the main component, The percentage of acidic and alkaline components; (7) The relative binding activity of the anti-TIGIT antibody to the TIGIT antigen in the antibody preparation is determined by direct ELISA.
  • SEC-HPLC size exclusion high performance liquid chromatography
  • the mobile phase is phosphate buffer (weigh 3.12g sodium dihydrogen phosphate dihydrate, 8.77g sodium chloride and 34.84g arginine, after dissolving in ultrapure water, adjust the pH to 6.8 with hydrochloric acid And dilute to 1000ml), the column protection solution is 0.05% (w/v) NaN 3 , the injection volume is 50 ⁇ l, the flow rate is 0.5ml/min, the collection time is 30 minutes, the column temperature is 25°C, and the detection wavelength is 280nm. Take the sample to be tested and dilute it to 2mg/ml with ultrapure water as the test solution. Take the preparation buffer solution and dilute it with the same treatment method as above and use it as a blank solution. Take 50 ⁇ l each of the blank solution and the test solution into the liquid chromatograph to start the test.
  • phosphate buffer weigh 3.12g sodium dihydrogen phosphate dihydrate, 8.77g sodium chloride and 34.84g arginine, after dissolving in ultrapure water
  • the capillary is an uncoated capillary with an inner diameter of 50 ⁇ m, a total length of 30.2cm, and an effective length of 20.2cm. Wash the capillary column with 0.1mol/L sodium hydroxide, 0.1mol/L hydrochloric acid, ultrapure water, and 70psi electrophoresis gel before electrophoresis.
  • Sample injection conditions -5kV for 20 seconds; separation voltage: -15kV for 35 minutes.
  • the capillary column temperature is controlled at 25°C, and the detection wavelength is 220nm.
  • mobile phase A is 10mmol/L phosphate buffer (weigh NaH2PO4 ⁇ 2H2O 0.51g, Na2HPO4 ⁇ 12H2O 2.40g dissolved in 800ml ultrapure water, dilute to 1000ml, Use ⁇ 0.22 ⁇ m membrane filter), mobile phase B is 10mmol/L phosphate + 200mmol/L sodium chloride buffer (weigh NaH2PO4 ⁇ 2H2O 0.51g, Na2HPO4 ⁇ 12H2O 2.40g, NaCl 11.69g dissolved in 800ml ultrapure In water, dilute to 1000ml, filter with ⁇ 0.22 ⁇ m membrane).
  • a 96-well microtiter plate was coated with human TIGIT antigen (purchased from Acrobiosystems, TIT-H52H3) at 0.5 ⁇ g/ml, 100 ⁇ l/well, 4°C overnight. After washing the plate, add blocking solution (2%BSA-PBST, 300 ⁇ l/well) at 37°C for 2h. Add 100 ⁇ l/well of the test substance in gradient dilution to the ELISA plate where the blocking solution is discarded. Set the negative control to add 100 ⁇ l diluent (2%BSA-PBST) to each well, and incubate in a constant temperature incubator at 37°C for 60min.
  • human TIGIT antigen purchased from Acrobiosystems, TIT-H52H3
  • HRP-conjugated goat anti-human IgG-Fc fragment (BETHYL, USA, catalog number A80-104P) diluted with 2% BSA-PBST was added as a secondary antibody (100000 times dilution, 100 ⁇ l/well), and reacted at 37°C for 30 min.
  • After washing the plate add 100 ⁇ l of TMB color developing solution to each well.
  • After 10 minutes of color development add 100 ⁇ l of 1mol/L H 2 SO 4 to each well to stop the reaction. Measure the OD value at 450nm with 620nm as the reference wavelength.
  • a concentration value of each sample as the abscissa the concentration gradient, OD450nm-OD620nm value for the vertical gradient of each sample, four parameter fit calculation application Prism EC 50 reflects the binding activity of the antibody with the antigen.
  • Opposing anti-TIGIT antibody binding activity (%) (test sample for the EC 50 / EC reference article 50) * 100%, wherein the reference product is not stable any stress processing.
  • the anti-TIGIT antibody ADI-30278 that specifically binds to TIGIT was obtained.
  • the antibody has the heavy chain sequence of SEQ ID NO: 9 and the light chain sequence of SEQ ID NO: 10, and is a fully human antibody.
  • PCT application number PCT/CN2019/097665 is hereby incorporated by reference in its entirety.
  • antibodies are recombinantly expressed in CHO cells and purified through processes such as filtration, chromatography, virus inactivation, and filtration.
  • the sample used for the following pH screening test is a product purified by affinity chromatography with a protein content of 17.0 mg/ml.
  • the sample used for the following prescription determination test is a product purified by nanofiltration membrane filtration and has a protein content of 11.5 mg/ml.
  • the judgment standard of the quality of the sample detection index value compared with the initial value is set to judge whether the sample has changed.
  • the judgment standard is shown in Table 2.
  • Test items Judgment criteria unchanged Appearance (observation method) Clear to slightly opalescent, colorless to light yellow liquid, no foreign matter Visible foreign body (Visible foreign body inspection method) Comply with "The Pharmacopoeia of the People's Republic of China" (2015 edition, four), 0904 Protein content (UV method) Change rate ⁇ 10% Turbidity (OD 350nm method) Change value ⁇ 0.02 Purity (SEC-HPLC method) Change of main peak ⁇ 1% Purity (non-reduced CE-SDS method) Change of main peak ⁇ 2% Charge variant (CEX-HPLC method) Change value of main component and each component of acid and alkali ⁇ 2% Relative binding activity (direct ELISA method) Should be 70% ⁇ 130%
  • the test results of protein content are shown in Table 3. The results showed that the protein content of the samples at pH 5.0, pH 5.5, and pH 6.0 did not change significantly after being placed at 40°C ⁇ 2°C for 2 weeks.
  • N/A means that the test is not set.
  • N/A means that the test is not set.
  • formulation 2 was finally selected as the antibody formulation formulation.
  • Its composition is: 50.0mg/ml recombinant fully human anti-TIGIT antibody, 0.21mg/ml histidine, 1.81mg/ml histidine hydrochloride, 25.00mg/ml sorbitol, 17.91mg/ml arginine hydrochloride, 0.50 mg/ml polysorbate 80, pH 5.2.

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Abstract

L'invention concerne des préparations qui contiennent un anticorps anti-TIGIT, les préparations contenant un anticorps anti-TIGIT, une solution tampon, un stabilisant et un tensioactif. De plus, l'invention concerne également l'utilisation de ces préparations dans le traitement ou la prévention de maladies.
PCT/CN2021/072690 2020-01-21 2021-01-19 Préparations d'anticorps monoclonaux anti-tigit recombinants entièrement humains, leur procédé de préparation et leur utilisation WO2021147854A1 (fr)

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US17/793,503 US20230080706A1 (en) 2020-01-21 2021-01-19 Recombinant fully human anti-tigit monoclonal antibody formulation, method for preparing same and use thereof
EP21744016.3A EP4094777A4 (fr) 2020-01-21 2021-01-19 Préparations d'anticorps monoclonaux anti-tigit recombinants entièrement humains, leur procédé de préparation et leur utilisation
CN202180010322.2A CN115052622A (zh) 2020-01-21 2021-01-19 重组全人源抗tigit单克隆抗体制剂及其制备方法和用途
CA3168600A CA3168600A1 (fr) 2020-01-21 2021-01-19 Preparations d'anticorps monoclonaux anti-tigit recombinants entierement humains, leur procede de preparation et leur utilisation
AU2021211799A AU2021211799A1 (en) 2020-01-21 2021-01-19 Recombinant fully human anti-TIGIT monoclonal antibody preparations, preparation method therefor and use thereof
JP2022544137A JP2023511356A (ja) 2020-01-21 2021-01-19 組換え完全ヒト抗ｔｉｇｉｔモノクローナル抗体製剤及びその調製方法と使用

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